Endpoints in NASH Clinical Trials: Are We Blind in One Eye?
This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/14/1/40 |
| _version_ | 1797339620017438720 |
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| author | Amedeo Lonardo Stefano Ballestri Alessandro Mantovani Giovanni Targher Fernando Bril |
| author_facet | Amedeo Lonardo Stefano Ballestri Alessandro Mantovani Giovanni Targher Fernando Bril |
| author_sort | Amedeo Lonardo |
| collection | DOAJ |
| description | This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular–kidney–metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone. |
| first_indexed | 2024-03-08T09:50:57Z |
| format | Article |
| id | doaj.art-7dc9b6f65dae4d9f827df76c4b5d6fee |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-08T09:50:57Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-7dc9b6f65dae4d9f827df76c4b5d6fee2024-01-29T14:04:53ZengMDPI AGMetabolites2218-19892024-01-011414010.3390/metabo14010040Endpoints in NASH Clinical Trials: Are We Blind in One Eye?Amedeo Lonardo0Stefano Ballestri1Alessandro Mantovani2Giovanni Targher3Fernando Bril4AOU—Modena—Ospedale Civile di Baggiovara, 41126 Modena, ItalyASL Modena—Ospedale di Pavullo, 41026 Pavullo nel Frignano, ItalySection of Endocrinology and Diabetes, Department of Medicine, University of Verona, Piazzale Stefani, 37126 Verona, ItalyDepartment of Medicine, University of Verona, 37126 Verona, ItalyDepartment of Medicine, Heersink School of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USAThis narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular–kidney–metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.https://www.mdpi.com/2218-1989/14/1/40biomarkerscardiovascular riskliver biopsymetabolic dysfunctionnatural history |
| spellingShingle | Amedeo Lonardo Stefano Ballestri Alessandro Mantovani Giovanni Targher Fernando Bril Endpoints in NASH Clinical Trials: Are We Blind in One Eye? Metabolites biomarkers cardiovascular risk liver biopsy metabolic dysfunction natural history |
| title | Endpoints in NASH Clinical Trials: Are We Blind in One Eye? |
| title_full | Endpoints in NASH Clinical Trials: Are We Blind in One Eye? |
| title_fullStr | Endpoints in NASH Clinical Trials: Are We Blind in One Eye? |
| title_full_unstemmed | Endpoints in NASH Clinical Trials: Are We Blind in One Eye? |
| title_short | Endpoints in NASH Clinical Trials: Are We Blind in One Eye? |
| title_sort | endpoints in nash clinical trials are we blind in one eye |
| topic | biomarkers cardiovascular risk liver biopsy metabolic dysfunction natural history |
| url | https://www.mdpi.com/2218-1989/14/1/40 |
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